Control of Yeast Life Span

热量限制（CR），即减少每天的热量摄入，可以延长小鼠和酵母的寿命。长期以来，CR一直被认为通过减少细胞能量代谢产生的活性氧（ROS）的数量来延长寿命。目前尚不清楚CR是否只是减少ROS的产生，还是还诱导了一种保护细胞免受ROS潜在损伤的状态。我们对酵母沉默控制的研究为CR的分子机制提供了新的见解。沉默，基因表达的可逆抑制，衰老酵母的变化，在酵母对CR的反应中起作用。我们分离了模仿衰老酵母沉默表型的突变。值得注意的是，我们发现了已知的增加酵母寿命的突变，并确定了与小鼠通路同源的通路，其表达在CR和衰老过程中发生变化。60%的突变体线粒体有缺陷，这是哺乳动物细胞衰老的标志。因此，我们对控制沉默的遗传途径的鉴定也鉴定了小鼠中CR和衰老调节的途径。我们还分离出了第二组突变，这些突变阻断了衰老酵母的沉默表型。这些突变体识别染色质重塑因子和染色质成分。染色质的改变可能是响应CR调节转录的途径的终点。因此，我们的两组突变体最有可能确定控制寿命的途径的信号产生和信号响应端。本研究的目的是了解基因沉默和寿命是如何在线粒体和CR缺陷的情况下被控制的。我们假设CR和我们的突变体诱导了细胞通常用来应对能量来源变化的途径，并通过特定的染色质成分来控制衰老速度。为了验证这些假设，我们将追求以下具体目标：目标1。我们的突变体确定了什么样的寿命和沉默调节途径？目标2。我们对沉默突变的控制是否以与CR相同的方式延缓衰老表型的出现？目标3。哪些延长寿命的基因是由CR控制的，以及在目标1和目标2中确定和表征的途径？本研究结果将阐明cr介导的寿命延长的分子机制，并为哺乳动物系统提供一个模型。

Caloric restriction (CR), i.e. the reduction of the daily caloric intake, can prolong the life span of mice and yeast. CR has long been thought to extend life span by reducing the number of reactive oxygen species (ROS) produced by cellular energy metabolism. It is not known if CR only reduces the production of ROS or also induces a state that protects the cell from potential damage from ROS. Our studies on the control of yeast silencing provide novel insights into the molecular mechanisms of CR. Silencing, the reversible repression of gene expression, changes in old yeast and plays a role in the yeast response to CR. We isolated mutations that mimic the silencing phenotype of aged yeast. Remarkably, we found mutations known to increase yeast life span and identified pathways homologous to mouse pathways whose expression changes during CR and aging. 60 percent of our mutants have defective mitochondria, a hallmark of aging in mammalian cells. Thus, our identification of genetic pathways that control silencing has also identified pathways modulated by CR and aging in mice. We have also isolated a second set of mutations that block the silencing phenotype of aged yeast. These mutants identify a chromatin remodeling factor and chromatin components. Changes in chromatin are the likely endpoints of pathways that modulate transcription in response to CR. Thus, our two sets of mutants most likely identify signal generating and signal responding ends of pathways that control life span. The goal of this proposal is to understand how gene silencing and life span are controlled in response to defective mitochondria and CR. We hypothesize that CR and our mutants induce pathways that the cell normally uses to respond to changes in energy source, and to control the rate of aging through specific chromatin components. To test these hypotheses, we will pursue the following specific aims: Aim 1. What life span- and silencing-modulating pathways do our mutants identify? Aim 2. Do our control of silencing mutations delay the appearance of aging phenotypes in the same way as CR? Aim 3. Which life span extending genes are controlled by CR and the pathways identified and characterized in aims 1 and 2? The results of this work will elucidate the molecular mechanisms of CR-mediated life span extension and provide a model for mammalian systems.